Triphalangeal thumb-polysyndactyly syndrome (TPT-PS) is a rare well-defined autosomal dominant disorder characterized by long thumbs with three phalanges combined with pre- and postaxial polydactyly/syndactyly of limbs. By now, the syndrome has been reported in several large families from different ethnic backgrounds, with a high degree of inter- and intrafamilial variability. The genome locus responsible for TPT-PS has been mapped to the 7q36.3 region harboring a long-range sonic hedgehog (SHH) regulatory sequence (ZRS). Both single-nucleotide variants and complete duplications of ZRS were shown to cause TPT-PS and similar limb phenotypes. TPT-PS usually forms as isolated limb pathology not associated with additional malformations, in particular, with cardiovascular abnormalities. Here we report on a rare Russian neonatal case of TPT-PS combined with severe congenital heart disease, namely double outlet right ventricle, and microphthalmia with optic disc coloboma. Pedigree analysis revealed TPT-PS of various expressivity in 10 family members throughout five generations, while the cardiac defect and the eye pathology were detected only in the proband. To extend the knowledge on genotype–phenotype spectrum of TPT-PS, the careful clinical and genomic analysis of the family was performed. High-resolution array-based comparative genomic hybridization (array-CGH) revealed a ~ 300 kb microduplication of 7q36.3 locus (arr[GRCh37] 7q36.3(156385810_156684811) × 3) that co-segregated with TPT-PS in the proband and her mother. The duplication encompassed three genes including LMBR1, the intron 5 of which is known to harbor ZRS. Based on whole-exome sequencing data, no additional pathogenic mutations or variants of uncertain clinical significance were found in morbid cardiac genes or genes associated with a microphthalmia/anophthalmia/coloboma spectrum of ocular malformations. The results support the previous data, indicating that complete ZRS duplication underlies TPT-PS, and suggest a broader phenotypic impact of the 7q36.3 microduplication. Potential involvement of the 7q36.3 microduplication in the patient’s cardiac and eye malformations is discussed. However, the contribution of some additional genetic/epigenetic factors to the complex patient`s phenotype cannot be excluded entirely. Further comprehensive functional studies are needed to prove the possible involvement of the 7q36.3 locus in congenital heart disease and eye pathology.

中文翻译：

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伴有先天性心脏病和视神经盘性结肠炎的三足指拇指多发性综合征的患者的7q36.3的300 kb微复制：一个病例报告

三趾角多指综合征（TPT-PS）是一种罕见的定义明确的常染色体显性遗传病，其特征是长拇指，三指和四肢前/后多指/趾联合。到现在为止，已经在来自不同种族背景的几个大家庭中报告了该综合征，其家族间和家族内差异很大。负责TPT-PS的基因组基因座已映射到7q36.3区域，该区域具有远程音速刺猬（SHH）调控序列（ZRS）。ZRS的单核苷酸变体和完全重复均显示导致TPT-PS和相似的肢体表型。TPT-PS通常以孤立的肢体病理形式形成，与其他畸形（尤其是心血管异常）无关。在这里，我们报道了俄罗斯罕见的TPT-PS合并严重先天性心脏病的新生儿病例，即双出口右心室和视神经盘状小脑膜炎的小眼症。家谱分析显示，在整个5代中的10个家庭成员中，TPT-PS的表达均不同，而心脏缺陷和眼部病理仅在先证者中被检测到。为了扩展有关TPT-PS基因型-表型谱的知识，对该家族进行了仔细的临床和基因组分析。基于高分辨率阵列的比较基因组杂交（阵列-CGH）显示〜300 kb的7q36.3基因座（arr [GRCh37] 7q36.3（156385810_156684811）×3）的微复制与先证者中的TPT-PS共分离和她的母亲。该重复包含三个基因，包括LMBR1，已知其内含子5带有ZRS。根据全外显子组测序数据，在病态心脏基因或与眼畸形的小眼/无眼/大眼瘤谱相关的基因中未发现其他致病突变或具有不确定临床意义的变体。结果支持以前的数据，表明完整的ZRS复制是TPT-PS的基础，并表明7q36.3微复制具有更广泛的表型影响。讨论了7q36.3微复制在患者心脏和眼睛畸形中的潜在参与。但是，不能完全排除某些其他遗传/表观遗传因素对复杂患者表型的贡献。需要进一步的综合功能研究来证明7q36.3基因座可能与先天性心脏病和眼部病理有关。在病态心脏基因或与眼畸形的小眼/无眼/结肠炎谱相关的基因中未发现其他致病突变或具有不确定临床意义的变异。结果支持以前的数据，表明完整的ZRS复制是TPT-PS的基础，并表明7q36.3微复制具有更广泛的表型影响。讨论了7q36.3微复制在患者心脏和眼睛畸形中的潜在参与。但是，不能完全排除某些其他遗传/表观遗传因素对复杂患者表型的贡献。需要进一步的综合功能研究来证明7q36.3基因座可能与先天性心脏病和眼部病理有关。在病态心脏基因或与眼畸形的小眼科/无眼科/结肠炎谱相关的基因中未发现其他致病突变或具有不确定临床意义的变体。结果支持以前的数据，表明完整的ZRS复制是TPT-PS的基础，并表明7q36.3微复制具有更广泛的表型影响。讨论了7q36.3微复制在患者心脏和眼睛畸形中的潜在参与。但是，不能完全排除某些其他遗传/表观遗传因素对复杂患者表型的贡献。需要进一步的综合功能研究来证明7q36.3基因座可能与先天性心脏病和眼部病理有关。